EP0455119A2 - Process for the preparation of canthaxanthin and astaxanthin - Google Patents

Abstract

Process for the preparation of canthaxanthine (Ia) and astaxanthine (Ib) of the general formula I …<IMAGE>… in which R represents H (a) or OH (b), which process is characterised in that a tertiary alcohol of the general formula II …<IMAGE>… in which R represents H (a) or OH (b), is reacted with trifluoroacetic acid, the novel trifluoroacetate obtained of the general formula III …<IMAGE>… is reacted with triphenylphosphine, the novel triphenylphosphonium trifluoroacetate obtained of the general formula IV …<IMAGE>… is reacted with 2,7-dimethyl-2,4,6-octatriene-1,8-dial under the conditions of a Wittig synthesis. In addition, the invention relates to the novel trifluoroacetates of the formula III and the corresponding triphenylphosphonium trifluoroacetates of the formula IV.

Description

The invention relates to a new process for the preparation of the sought-after carotenoids canthaxanthin (Ia) and astaxanthin (Ib).

A repeatedly described synthesis concept for these two carotenoids is based on the double Wittig condensation of a corresponding C₁ eines-phosphonium salt with the symmetrical C₁₀-dialdehyde 2,7-dimethyl-2,4,6-octatrien-1,8-dial.

According to the prior art, the halides of the formula below are used as C₁₅-phosphonium salts, the bromide in particular being used as the anion of the phosphonium salt.

mit Triphenylphosphin hergestellt.The phosphonium salts suitable according to the above-described synthesis principle C₁₅ + C₁₀ + C₁ nach as C₁₅ building blocks for canthaxanthin or astaxanthin are obtained by reacting the corresponding allyl bromides of the formula

made with triphenylphosphine.

in der R für H (a) oder OH (b) steht.One access to the allyl bromides mentioned is the halogenating allyl rearrangement of the tertiary alcohols of the formula II

in which R represents H (a) or OH (b).

This synthetic route, which has been described several times in the literature, has serious disadvantages in practical implementation with regard to process engineering requirements and economy.

For example, the conversion of the tertiary alcohol of the formula IIb to the corresponding allyl bromide at low temperature (according to EP 101 597 at -20 ° C to -10 ° C; EP 5749 at + 5 ° C and according to Helv. Chim. acta 64 (1981), page 2430 at 0 ° C) by reaction with 63% aqueous hydrobromic acid, a considerable excess of hydrogen bromide (2.5-4 equivalents) being required. According to Helv. Chim. acta 64 (1981), pages 2430 and 2440, the reaction must be carried out at low temperature and very quickly in order to avoid decomposition of the not very stable allyl bromide and to keep the rearrangement of the α-hydroxyketone into the diosphenol.

In the further processing of the allyl bromide, butylene oxide must also be added several times to trap acid traces.

For the production of canthaxanthin, the tertiary alcohol of the formula IIa is converted by treatment with phosphorus tribromide in an inert organic solvent into the corresponding allyl bromide, from which the corresponding phosphonium salt is obtained by reaction with triphenylphosphine (DE-OS 2 801 908) . Here too, a considerable excess (≧ 3 equivalents) has to be used on the expensive halogenating agent. As an alternative to bromination with phosphorus tribromide and subsequent reaction with triphenylphosphine, the triphenylphosphonium bromide can also be prepared directly from the tertiary alcohol of the formula IIa by reaction with triphenylphosphine hydrobromide (cf. DE-OS 2 801 908). However, this reagent must be prepared in an additional step from triphenylphosphine and HBr and must also be used in a considerable excess.

In J. Org. Chem. 47 (1982) page 2133, the best production method for this C₁₅-triphenylphosphonium salt is the reaction of the tertiary alcohol of the formula IIa with triphenylphosphine hydrobromide, the hydrobromide being used in an excess of 17 mol% .

A disadvantage of the processes according to the prior art is that, in any case, considerable excesses of expensive halogenation agents which are not problematic in terms of process technology must be used for the conversion of the tertiary alcohols of the formula II to the corresponding triphenylphosphonium bromides. In the case of the production of astaxanthin, the low stability of the corresponding allyl bromide is another problem.

It was therefore the object of the invention to develop a process for the production of canthaxanthin and astaxanthin in which the disadvantages of the prior art do not occur.

It has now surprisingly been found that the tertiary alcohols of the formula II by treatment with trifluoroacetic acid smooth into the new trifluoroacetates of the formula III and these by subsequent reaction with Triphenylphosphine can be converted into the phosphonium salts of formula IV. The practical procedure is identical for both starting materials, which means a further considerable technical advantage for this new process.

in der R für H (a) oder OH (b) steht, das dadurch gekennzeichnet ist, daß man

• A. einen tertiären Alkohol der allgemeinen Formel II
  
  in der R für H (a) oder OH (b) steht, mit Trifluoressigsäure umsetzt,
• B. das erhaltene neue Trifluoracetat der allgemeinen Formel III
  
  mit Triphenylphosphin umsetzt,
• C. das erhaltene neue Triphenylphosphoniumtrifluoracetat der allgemeinen Formel IV

in der R für H (a) oder OH (b) steht,
mit 2,7-Dimethyl-2,4,6-octatrien-1,8-dial unter den Bedingungen einer Wittigsynthese umsetzt.The invention therefore relates to a process for the preparation of canthaxanthin (Ia) and astaxanthin (Ib) of the general formula I.

in which R represents H (a) or OH (b), which is characterized in that

• A. a tertiary alcohol of the general formula II
  
  in which R represents H (a) or OH (b), reacted with trifluoroacetic acid,
• B. the new trifluoroacetate obtained of the general formula III
  
  reacted with triphenylphosphine,
• C. the new triphenylphosphonium trifluoroacetate obtained of the general formula IV

in which R represents H (a) or OH (b),
reacted with 2,7-dimethyl-2,4,6-octatriene-1,8-dial under the conditions of a Wittigsynthesis.

The invention also relates to the new intermediates of the formulas III and IV which enable the advantageous new process.

The reaction of the tertiary alcohols of the formula II with trifluoroacetic acid is generally carried out in an inert organic solvent, such as methylene chloride, 1,2-dichloroethane or ethyl acetate, at temperatures from about 0 ° C. to + 50 ° C., preferably 10-30 ° C., in particular at room temperature. Only 1.0-1.05 equivalents of trifluoroacetic acid, based on the alcohols of the formula II, are required here. The new trifluoroacetates of the formula III are obtained in a smooth reaction and in good yields, without the secondary hydroxyl group of IIIb being esterified and without the risk that the α-ketol is rearranged into the diosphenol.

The crude trifluoroacetates of the formula III can be further processed directly to the phosphonium salts of the formula IV, for example by heating with a triarylphosphine, in particular triphenylphosphine, in an inert organic solvent such as toluene, ethyl acetate or methylene chloride. This reaction can be carried out particularly easily by heating the crude trifluoroacetates in bulk without the addition of a solvent with triphenylphosphine.

The triphenylphosphine is generally used in amounts of 1.0 to 1.2 moles per mole of trifluoroacetate of the formula III. The reaction is generally carried out at from room temperature to the reflux temperature of the solvent used, preferably at from about 50 to 100.degree. The reaction time is, for example, about 15 to 30 minutes when the reaction is carried out without a solvent in the temperature range from 80 to 100 ° C.

The crude phosphonium salt of the formula IV obtained in this way can be purified by precipitation from a suitable organic solvent, such as methyl tert-butyl ether (MTB) or diisopropyl ether.

The carotenoids canthaxanthin Ia are obtained from the phosphonium salts of the formula IVa or IVb by reaction with the C₁₀ dialdehyde 2,7-dimethyl-2,4,6-octatriene-1,8-dial under the reaction conditions typical of such Wittig condensations or astaxanthin Ib in good yields.

For more details on the reaction conditions for Wittig reactions, we refer, for example, to J. Org. Chem. 47 (1982) pages 2130-2134 and Helv. Chim. Acta 64 (1981) pages 2436ff.

The following examples are intended to explain the process according to the invention.

example 1 A. Preparation of 5- [2,6,6-trimethyl-3-oxo-1-cyclohexen-1-yl] -3-methyl-2,4-pentadien-1-ol-trifluoroacetate (IIIa)

10.0 g (42.7 mmol) 5- [2,6,6-trimethyl-3-oxo-1-cyclohexen-1-yl] -3-methyl-3-hydroxy-1,4-pentadiene (IIa) were dissolved in 40 ml of methylene chloride and 4.4 ml (43.2 mmol) of trifluoroacetic acid (D 1.12) were added dropwise at 0.degree. The reaction mixture was then allowed to come to room temperature (RT) and stirred at RT for 3 hours (h).

The mixture was then poured onto water. The organic phase was separated off and the water phase was extracted again with methylene chloride. The combined organic phases were washed with dilute sodium hydrogen carbonate solution and dried over sodium sulfate. After the solvent had been stripped off on a rotary evaporator, 12 g of trifluoroacetate IIIa were obtained as a reddish-colored oil. IR spectrum (film): 1784 cm⁻¹ (vs), 1665 cm⁻¹ (s), 1217 cm⁻¹ (vs), 1168 cm⁻¹ (vs).

B. Preparation of 5- [2,6,6-Trimethyl-3-oxo-1-cyclohexen-1-yl] -3-methyl-2,4-pentadien-1-yl-triphenylphosphonium trifluoroacetate (IVa)

The crude trifluoroacetate IIIa was stirred together with 9.5 g triphenylphosphine for 30 minutes (min) in a preheated oil bath at a bath temperature of 100-120 ° C. The residue was allowed to cool and the crude phosphonium salt was dissolved in methylene chloride. By adding this solution dropwise to methyl tert-butyl ether (MTB), the triphenylphosphonium salt IVa precipitated out in the form of white crystals. Mp .: 150-154 ° C

C. Preparation of canthaxanthin (Ia)

5.3 g of the phosphonium salt IVa and 500 mg of 2,7-dimethyl-2,4,6-octatriene-1,8-dial were dissolved in 25 ml of methylene chloride. The mixture was cooled to 0 ° C., 1.6 g of a 30% strength methanolic solution of sodium methylate were added dropwise to the mixture, the mixture was allowed to come to RT and the mixture was stirred for 2 hours. The mixture was then poured onto water. The organic phase was separated and the water phase was extracted with methylene chloride. The combined organic phases were dried over sodium sulfate and concentrated on a rotary evaporator. The residue was taken up in 20 ml of methanol and heated to boiling under reflux for 30 min, then cooled to 0 ° C. and the precipitated canthaxanthin was filtered off.

Weight: 1.1 g canthaxanthin

A further 0.4 g of canthaxanthin was obtained by column chromatography purification of the mother liquor.

Example 2 A. Preparation of 5- [2,6,6-trimethyl-3-oxo-4-hydroxy-1-cyclohexen-1-yl] -3-methyl-2,4-pentadien-1-ol-trifluoroacetate (IIIb)

8 g (32 mmol) of 5- [2,6,6-trimethyl-3-oxo-4-hydroxy-1-cyclohexen-1-yl] -3-methyl-3-hydroxy-1,4-pentadiene (IIb) were dissolved in 25 ml of methylene chloride. 3.7 g (32.5 mmol) of trifluoroacetic acid were added dropwise at 0.degree. The mixture was allowed to come to RT and stirred at RT for 5 h. The mixture was then poured onto dilute sodium hydrogen carbonate solution. The organic phase was separated off and the water phase was extracted again with methylene chloride. The combined organic phases were washed with dilute hydrogen carbonate solution and dried over sodium sulfate. After stripping off the solvent on a rotary evaporator, 9-10 g of trifluoroacetate IIIb were obtained as a crude oil. IR spectrum (film): 3500 cm⁻¹ (broad), 1784 cm⁻¹ (vs), 1670 cm⁻¹ (s), 1221 cm⁻¹ (s), 1168 cm⁻¹ (vs), 1149 cm⁻ 1 (vs).

B. Preparation of 5- [2,6,6-Trimethyl-3-oxo-4-hydroxy-1-cyclohexen-1-yl] -3-methyl-2,4-pentadien-1-yl-triphenylphosphonium trifluoroacetate ( IVb)

1.3 g of the crude trifluoroacetate IIIb obtained were stirred with 1.0 g of triphenylphosphine in a preheated oil bath at a bath temperature of 100 ° C. for 30 minutes. The residue was allowed to cool, the crude phosphonium salt was dissolved in ethyl acetate and the solution was again added dropwise to MTB. The precipitate was separated and dried under reduced pressure. 1.3-1.4 g of the triphenylphosphonium salt IVb were obtained as a light yellow foam.

The phosphonium salt IVb was obtained in the form of colorless crystals by redissolving in ethyl acetate and dropwise adding MTB. Mp .: 147-148 ° C, calculated fluorine value: 9.4%, analytically determined fluorine value: 9.5%.

C. Preparation of Astaxanthin (Ib)

8.4 g of the crystalline phosphonium salt IVb and 760 mg of 2,7-dimethyl-2,4,6-octatriene-1,8-dial were dissolved in 33 ml of methylene chloride. The mixture was cooled to 0 ° C., 2.24 g of a 30% strength methanolic solution of sodium methylate was added dropwise to the mixture, the temperature was allowed to rise to RT and the mixture was stirred for a further 3 1/2 hours. The reaction mixture was then poured onto water. The organic phase was separated off and the water phase was extracted again with methylene chloride. The combined organic phases were washed with water, dried over sodium sulfate and concentrated on a rotary evaporator. Clean astaxanthin was obtained by purifying the crude product by column chromatography.

Weight: 2.3 g astaxanthin.

Claims (3)

Process for the preparation of canthaxanthin (Ia) and astaxanthin (Ib) of the general formula I

in which R is H (a) or OH (b), characterized in that A. a tertiary alcohol of the general formula II

in which R represents H (a) or OH (b), reacted with trifluoroacetic acid, B. the new trifluoroacetate obtained of the general formula III

reacted with triphenylphosphine, C. the new triphenylphosphonium trifluoroacetate obtained of the general formula IV

in which R represents H (a) or OH (b),
reacted with 2,7-dimethyl-2,4,6-octatriene-1,8-dial under the conditions of a Wittigsynthesis. Compounds of formula III

in which R represents H (a) or OH (b). Compounds of formula IV

in which R represents H (a) or OH (b).